There are several different classes of compounds which may have anti-ischemic properties under the right conditions. The mechanisms of action of many of these compounds are incompletely understood at best. Some of these compounds may act at different molecular sites, but ultimately may work via similar physiological mechanisms. Calcium antagonists are thought to be effective in reducing the severity of myocardial ischemia by their effects on reducing myocardial work as well as increasing blood flow to the ischemic region, Szekeres, L., et al., "Importance of myocardial flow changes in the protective action of diltiazem in a new model of myocardial ischemia." Br. J. Pharmacol 86:341-350, 1985; and Grover, G. and Parham, C. "The effect of diltiazem on ST-segment elevation and myocardial blood flow distribution during pacing-induced ischemia." Eur. J. Pharmacol 143:109-117, 1987. .beta.-Adrenoceptor antagonists such as propranolol can also reduce the severity of an ischemic episode and this may also occur via their effect on work or flow, Conway, R. and Weiss, H., "Role of propranolol in improvement of the relationship between O.sub.2 supply and consumption in an ischemic region of the dog heart." J. Clin. Invest. 70:320-329, 1982. Thus, one would not expect a combination of these two compounds to have additive effects above what one would expect from just increasing the dose of one or the other compound alone, unless other unknown protective mechanisms exist. One other problem is that combining these two classes of compounds may result in additive effects which may be contraindicated. An example would be the excessive hypotension and tachycardia which may be seen with .beta.-blockers and calcium antagonists. This would be contraindicated in patients in the critical care setting where cardiac function may already be severely compromised. Thus, multiple drug treatment of myocardial ischemia may be best when drugs of differing physiological mechanisms of action are used.
Recently, it has been shown that thromboxane receptor antagonists possess potent anti-ischemic properties which appear to occur independently of changes in heart work or blood flow, Grover, G. and Schumacher, W., "Effect of the thromboxane receptor antagonist SQ 29,548 on myocardial infarct size in dogs." J. Cardiovasc. Pharmacol. 11:29-35, 1988. The appear to work via a mechanism different from the calcium antagonists or .beta.-blockers.